Comparable Effectiveness of Cefuroxime and Piperacillin-Tazobactam as Empirical Therapy for Methicillin-Susceptible Staphylococcus aureus Bacteremia

ABSTRACT Our objective was to examine whether empirical antimicrobial therapy (EAT) against methicillin-susceptible Staphylococcus aureus bacteremia (MS-SAB) with piperacillin-tazobactam (TZP), cefuroxime or combination therapy with one of these was differentially associated with 7-, 30-, and 90- day all-cause mortality or MS-SAB relapse. A multicenter retrospective cohort study of adults with MS-SAB from 2009 through 2018 was used, and 7-, 30-, 90-day mortality and relapse within 90 days were assessed and expressed as hazard ratio (HR) with a 95% confidence interval (95% CI) using Cox proportional hazard regression analysis. Matching of the two monotherapy groups was performed using propensity score matching. In total, 1158 MS-SAB cases were included and received one of three EAT regimens: TZP (n = 429), cefuroxime (n = 337), or TZP or cefuroxime with one or more additional effective antimicrobial (n = 392). The overall 30-day mortality was 28.0% (25.5 to 30.3%). After adjustment and matching, there was no significant difference in 7-, 30-, or 90-day mortality between the therapy groups. The matched HR of death was 0.81 (95% CI, 0.38 to 1.76) at 7 days, 0.82 (95% CI, 0.47 to 1.46) at 30 days, and 0.81 (95% CI, 0.50 to 1.32) at 90 days for TZP compared with cefuroxime. Adjusted HR of 90-day relapse was insignificant between the three therapy groups: TZP: 1.55 (95% CI, 0.54 to 4.43); combination therapy: 1.73 (95% CI, 0.62 to 4.80) compared to cefuroxime. There was no significant difference in 7-, 30-, or 90-day mortality or relapse between MS-SAB patients treated with empirical TZP or cefuroxime after adjustment and matching of covariables. IMPORTANCE This multicenter retrospective matched cohort study evaluated the effect of empirical antimicrobial therapy on the clinical outcome of methicillin-susceptible Staphylococcus aureus bacteremia (MS-SAB) in >1100 adult patients. To the best of our knowledge, this is the largest study to date evaluating the effect of empirical treatment on the MS-SAB outcome. Importantly, the study found no significant difference in either short- or long-term mortality nor relapse between patients with MS-SAB receiving empirical treatment with cefuroxime or piperacillin-tazobactam. As such, this study provides crucial contemporary data supporting the widespread clinical practice of initiating empirical antimicrobial therapy of sepsis with β-lactam-β-lactamase-inhibitor.

Introduction: -2nd paragraph: The statement that cefuroxime is considered to have a "comparable effect" to other cephalosporins is slightly misleading. The citation provided shows conflicting results in previous studies with a possible trend towards poorer outcomes.
-3rd paragraph: The authors could expand on potentially increased mortality with piperacillin/tazobactam treatment of MSSA to illustrate the need to clarify its role in SAB.
Methods: -For EAT, was initiation prior to reporting of the culture or initiation prior to culture collection required? Reporting may lag hours to days after culture was collected.
-Were any constraints on the duration of empiric therapy required (e.g., 24 hours)? Or was one dose or more acceptable?
-For the combination group, were there any stipulations to the timing and overlap of the agents? -Were polymicrobial blood cultures excluded (noted in Figure 1)? I recommend including a discussion of exclusions in the Methods.
-Define mortality in definitions. All-cause mortality?
-How were the indications for empirical defined/collected? How did this differ from the primary focus listed in Table 1? Results allude to how these were defined but not abundantly clear.
-For combination therapy, how was "effective" defined? Is this simply in vitro susceptibility?
-Is there more detail on the propensity scores for each group and how this was addressed in regression analysis?
-The PS matching resulted in significant attrition in the piperacillin/tazobactam group. Would the analysis be better served with comparative inverse probability of treatment weighting analysis? -Were any of the following confounders collected: source control, septic shock, duration of bacteremia, uncomplicated vs complicated SAB, time to defervescence, and time to effective therapy?
Results: -A significant amount of patients (~30%) were excluded due to receiving other regimens. What were these regimens? If antistaph penicillin or cephalosporin, would they have been an additional comparator group? -3rd sentence: Consider making % out of included cohort instead of the total cohort to provide reader appreciation of division amongst the three regimens for the study cohort.
-Several key differences (e.g., TTE, primary focus, duration of EAT, definitive drug therapy, etc.) could be highlighted in the text.
-No comparison tables are provided for characteristics shown in Table 1 for the PS matched cohorts. This makes it hard to appreciate the effectiveness of the matching. This could be included in supplemental materials.
-Authors provide subgroup characteristics for 3 days or more in Supplementary Figure 3 but not for <3 days. This would provide the reader the opportunity to appreciate if differences existed between the groups.
-A major limitation of the study is that the piperacillin/tazobactam group received a median of 1 day of therapy followed by a majority of patients receiving optimized definitive therapy (i.e., dicloxacillin and penicillin). However, the cefuroxime group received 2.5 days and ~50% were on definitive combination therapy (details not provided). In addition, ~10% of the piperacillin/tazobactam group received cefuroxime therapy as definitive therapy confounding the results. These items should be discussed further in the results and discussion.
Discussion: -Last paragraph: I would clarify 90-day relapse rate. Also, the same wording is found in the abstract.
-Were there significant changes in the standard of care for the management of SAB in the study countries over the time span other than changes in empiric therapy? Summary: This is a thoughtful multicenter retrospective cohort study that seeks to address the timely issue of empiric antimicrobial therapy, particularly the initiation of a beta-lactam, while balancing risk of mortality from S aureus bacteremia. The study is strengthened by its long study period and large cohort which increases the study's extrinsic validity. It is also enhanced by utilizing propensity matching to address confounding by indication, which strengthens the internal validity of the study. This allows readers to better understand how to contextualize the study's findings and apply them to their own practice.
To strength the paper, I would recommend commenting on the following: -The study's clarity could be enhanced with the addition of explanations or enhanced precision of language to certain terms such as "blood parameters" or the clinical or research relevance of identifying healthcare-associated SAB as a distinct entity.
-To further succinct and relevant communication of statistical information, consolidating tables such as 2 through five and reviewing how certain supplementary figures/tables or figures contribute to the results of interest. This would allow the addition of data that could not be shown to be presented and contribute further to the study's published findings.
Major essential revisions: Abstract and Importance Would state at the start that the study assesses MSSA rather than MRSA to ensure readers are aware of the pathogen at hand; international readers in areas with a predominance of MRSA may suppose MRSA over MSSA at the start. Methods Please clarify in the definitions why it was important to define a health-care associated SAB in contrast to hospital and community onset as health-care associated SAB is not brought up later in the paper as an entity with notably differences in clinical outcomes. Please provide exclusion criteria in this section. Would clarify whether "iv device infections" included both central line associated infections and peripheral access-associated, or only one of the two. Please clarify what is meant by "blood parameters" for the Pitt bacteremia score as there are temperature, blood pressure, mechanical ventilation, cardiac arrest, and mental status points but the terminology is not commonly used and could confuse some readers with its lack of specificity. Please clarify why two clinical scores were utilized and calculated. Please clarify why 3 days was chosen as the cutoff for duration of therapy.

Results:
Would recommend keeping description of inclusion and exclusion criteria to the methods section for paper organization. Line 201: Would a table of such findings be possible to present and if not, could the statistical results be summarized here?

Discussion
Line 264: Could the statistical results be presented to quantify what the "marginal impact" was? If so, this should be discussed in the results section. Would mention how the authors believe these results could be salient for practitioners outside of Denmark, given the international readership of the journal.
Minor essential revisions: Methods: Line 121: Would mention Supplemental Table 2 here when referencing effective combination regimens Line 129: Would consider providing an example of a diagnosis that falls into the "other" category. Line 146: Please define or provide an example of what is meant by a serious S. aureus infection Line 168: Exactly how many cases or controls were matched up against more than one case or control? For readers who may be unfamiliar with propensity score matching, would consider explaining briefly why multiple matches might have been required.
Results: Line 181-182: Consider providing a specific odds ratio to quantify how much more likely were the TZP monotherapy group to have a higher CCI. Would also be specific in saying CCI rather than comorbidity itself as the score is a cumulative measure. Line 183: Please consider providing a specific odds ratio to quantify how much more associated "skin, soft tissue or bone infection" was associated with cefuroxime alone.

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Review: Comparable effectiveness of cefuroxime and piperacillin/tazobactam as empirical therapy for Staphylococcus aureus bacteremia
Summary: This is a thoughtful multicenter retrospective cohort study that seeks to address the timely issue of empiric antimicrobial therapy, particularly the initiation of a beta-lactam, while balancing risk of mortality from S aureus bacteremia. The study is strengthened by its long study period and large cohort which increases the study's extrinsic validity. It is also enhanced by utilizing propensity matching to address confounding by indication, which strengthens the internal validity of the study. This allows readers to better understand how to contextualize the study's findings and apply them to their own practice.
To strength the paper, I would recommend commenting on the following: -The study's clarity could be enhanced with the addition of explanations or enhanced precision of language to certain terms such as "blood parameters" or the clinical or research relevance of identifying healthcare-associated SAB as a distinct entity.
-To further succinct and relevant communication of statistical information, consolidating tables such as 2 through five and reviewing how certain supplementary figures/tables or figures contribute to the results of interest. This would allow the addition of data that could not be shown to be presented and contribute further to the study's published findings.

Major essential revisions: Abstract and Importance
Would state at the start that the study assesses MSSA rather than MRSA to ensure readers are aware of the pathogen at hand; international readers in areas with a predominance of MRSA may suppose MRSA over MSSA at the start.

Methods
Please clarify in the definitions why it was important to define a health-care associated SAB in contrast to hospital and community onset as health-care associated SAB is not brought up later in the paper as an entity with notably differences in clinical outcomes. Please provide exclusion criteria in this section. Would clarify whether "iv device infections" included both central line associated infections and peripheral access-associated, or only one of the two. Please clarify what is meant by "blood parameters" for the Pitt bacteremia score as there are temperature, blood pressure, mechanical ventilation, cardiac arrest, and mental status points but the terminology is not commonly used and could confuse some readers with its lack of specificity. Please clarify why two clinical scores were utilized and calculated. Please clarify why 3 days was chosen as the cutoff for duration of therapy.

Results:
Would recommend keeping description of inclusion and exclusion criteria to the methods section for paper organization. Line 201: Would a table of such findings be possible to present and if not, could the statistical results be summarized here?

Discussion
Line 264: Could the statistical results be presented to quantify what the "marginal impact" was? If so, this should be discussed in the results section.

Dear editors and reviewers,
Following your letter regarding our manuscript "Comparable effectiveness of cefuroxime and piperacillin/tazobactam as empirical therapy for Staphylococcus aureus bacteremia", we hereby send this point-by-point response letter which explains the changes performed in the revised manuscript.
We would like to thank the reviewers for taking the time to evaluate our manuscript and for the insightful comments and suggestions. In addition, we would like to thank the editor for the opportunity to resubmit our revised manuscript.
Below is given a point-by-point response to the reviewer comments formatted in italic. Important changes in the revised manuscript are highlighted in yellow.

Reviewer #1
The manuscript by Bigseth and colleagues represents a multicenter retrospective study aimed to determine the equivalent effectiveness of cefuroxime and piperacillin/tazobactam for the treatment of Staphylococcus aureus bacteremia (SAB). The study includes a reasonable size cohort that has the potential to support empiric utilization of piperacillin/tazobactam for the management of sepsis.
However, the overall global applicability and interpretation are limited by the comparator (cefuroxime). In addition, several items require clarification to fully interpret the results.

Reviewer comment 1.1
Title: The authors should consider clarifying the type of SAB (i.e., PSSA, MSSA) in the title and throughout the manuscript.
Clarification is provided in the discussion when illustrating examples of other studies (i.e., MSSA).

Author response 1.1
Thank you for reviewing the manuscript. We agree that it should be stated more clearly that only cases of methicillin-susceptible SAB (MS-SAB) were included in the study. As such, the nomenclature has been changed to MS-SAB throughout the paper, including the title.

Regarding the choice of cefuroxime as the comparator drug to TZP, cefuroxime was chosen because it is the most used cephalosporin against MS-SAB and a prevalent EAT drug in general in
Denmark. There has also been a general assertion by clinicians in Denmark that cefuroxime is a better empirical drug against MSSA infections than TZP, which conflicts with the results of our study.
The title has been changed to:

Reviewer comment 1.2
Introduction: -2nd paragraph: The statement that cefuroxime is considered to have a "comparable effect" to other cephalosporins is slightly misleading. The citation provided shows conflicting results in previous studies with a possible trend towards poorer outcomes.

Author response 1.2
We agree with the reviewer that prior studies have found somewhat inconsistent results in studies The following has been changed in the manuscript: Few studies have investigated the effect of cefuroxime compared to other cephalosporins against MS-SAB and have reported inconsistent findings. (9)(10)(11) In Denmark, cefuroxime is the most frequently used cephalosporin against MS-SAB.

Reviewer comment 1.3
-3rd paragraph: The authors could expand on potentially increased mortality with piperacillin/tazobactam treatment of MSSA to illustrate the need to clarify its role in SAB.

Author response 1.3
Thank you for this comment. Prior studies have indicated that TZP is associated with higher 30-day all-cause mortality in patients with MS-SAB. (1,4) However, these studies were based on limited sample sizes and did not properly account for confounding by indication. As such, further investigations are required to conclude on the differential effect of empirical TZP or cefuroxime against MS-SAB.
The following has been changed in the manuscript: There are, however, some studies that have reported an increased risk of mortality in patients with MS-SAB treated with TZP compared to cephalosporins. (9,17) The sample size of these studies have been limited (n < 600), and as such, further investigations are needed to conclude on this matter.

Reviewer comment 1.4
Methods: -For EAT, was initiation prior to reporting of the culture or initiation prior to culture collection required? Reporting may lag hours to days after culture was collected.

Author response 1.4
Thank you for this comment. All drugs considered for EAT were initiated prior to reporting of blood culture test results. EAT was administrated immediately after blood cultures were performed for most SAB patients.

Reviewer comment 1.5
-Were any constraints on the duration of empiric therapy required (e.g., 24 hours)? Or was one dose or more acceptable?

Author response 1.5
Very relevant comment. We only included EAT which was continued for at least 24 hours. This has now been specified in the manuscript.
The following has been changed in the manuscript: EAT given < 24 hours was excluded.

Reviewer comment 1.6
-For the combination group, were there any stipulations to the timing and overlap of the agents?

Author response 1.6
Thank you for this comment. In general, the combination therapy group consisted of a very heterogeneous group of EAT regimens in terms of timing and duration of overlap of administered EAT drugs. The EAT drugs in the combination therapy group were registered as long as they were initiated before the results of the blood cultures became available. Thus, there were no constraints on whether they had to overlap in time of administration. As an example, if a patient received cefuroxime empirically on day one and two after admission and thereafter dicloxacillin empirically on day two and three before the blood culture was positive of MSSA later on day three, the patient was included in the combination therapy group.

Reviewer comment 1.7
-Were polymicrobial blood cultures excluded (noted in Figure 1)? I recommend including a discussion of exclusions in the Methods.

Author response 1.7
Thank you for this comment. Cases of polymicrobial bloodstream infections were excluded at baseline because this study solely focused on EAT for MS-SAB. An exclusion criteria paragraph with a clarification of polymicrobial bacteremia has been added to the Methods section.
The following has been changed in the manuscript:

Exclusion criteria
A case of MS-SAB was defined by the following: I) at least one positive blood culture of S. aureus and II) age > 18 years. Cases of MS-SAB suspected to be due to contamination, recurrent MS-SAB within the last 90 days or polymicrobial bacteremia were excluded at baseline. Cases with polymicrobial bacteremia were excluded because the study solely focused on EAT for MS-SAB.

Reviewer comment 1.8
-Define mortality in definitions. All-cause mortality?

Author response 1.8
Thank you for this comment. All-cause mortality was used in the primary outcome measures of this study, which has now been specified in the manuscript.
The following has been changed in the manuscript:

Clinical outcomes
Outcomes in the study were 7-, 30-and 90-day all-cause mortality and MS-SAB relapse.

Reviewer comment 1.9
-How were the indications for empirical defined/collected? How did this differ from the primary focus listed in Table 1? Results allude to how these were defined but not abundantly clear.

Author response 1.9
Thank you for this very relevant comment. Data on the indication for EAT was only registered if clearly stated in the medical record by the treating physician before blood culture test results became available. The primary focus of the infection was defined as the suspected primary focus of SAB after the blood culture test results were available. As such, the indication for EAT and the primary focus of the infection would likely be similar in most cases but not necessarily.
The following has been changed in the manuscript: Indications for EAT were solely defined by the treating physician who prescribed EAT and only registered if clearly stated in the medical record before blood culture results became available.

Reviewer comment 1.10
-For combination therapy, how was "effective" defined? Is this simply in vitro susceptibility?

Author response 1.10
Thank you for this comment.

Reviewer comment 1.15
-3rd sentence: Consider making % out of included cohort instead of the total cohort to provide reader appreciation of division amongst the three regimens for the study cohort.

Author response 1.15
Excellent suggestion. We have now added these percentages to the manuscript.
The following has been changed in the manuscript: Of included individuals, 429 (37.0 %) received piperacillin/tazobactam, 337 (29.1 %) received monotherapy with cefuroxime, and 392 (33.9 %) were treated with a combination of cefuroxime or TZP and at least one other anti-staphylococcal drug.

Reviewer comment 1.16
-Several key differences (e.g., TTE, primary focus, duration of EAT, definitive drug therapy, etc.) could be highlighted in the text.

Author response 1.16
We agree with the reviewer that these differences deserve further elaboration in the manuscript.
This has now been added, see below.
Regarding the duration of EAT and definitive drug therapy, please see author response 1.19.
The following has been changed in the manuscript:

Discussion
Our impression is that the use of diagnostic procedures, including echocardiography, has increased over the last decades. As such, the differences in the proportion of patients who underwent echocardiography in the two treatment groups are likely a consequence of the time periods in which the two regimens were predominantly administered (Figure 3). Moreover, the increasing use of echocardiography in the management of SAB could explain the higher rate of endocarditis in the TZP group compared to the cefuroxime group.

Reviewer comment 1.17
-No comparison tables are provided for characteristics shown in Table 1 for the PS matched cohorts. This makes it hard to appreciate the effectiveness of the matching. This could be included in supplemental materials.

Author response 1.17
We agree with the reviewer that more details on the characteristics of the propensity score-matched cohort would add significant information on the effectiveness of the matching process. As such, a

Reviewer comment 1.18
-Authors provide subgroup characteristics for 3 days or more in Supplementary Figure 3 but not for <3 days. This would provide the reader the opportunity to appreciate if differences existed between the groups.

Thank you for this relevant comment. A table including information on patients receiving less than
three days of EAT with cefuroxime or TZP has been added to the manuscript.
The following has been changed in the manuscript:

Reviewer comment 1.19
-A major limitation of the study is that the piperacillin/tazobactam group received a median of 1 day of therapy followed by a majority of patients receiving optimized definitive therapy (i.e., dicloxacillin and penicillin). However, the cefuroxime group received 2.5 days and ~50% were on definitive combination therapy (details not provided). In addition, ~10% of the piperacillin/tazobactam group received cefuroxime therapy as definitive therapy confounding the results. These items should be discussed further in the results and discussion.

Author response 1.19
Thank you for this insightful comment. We agree that the difference in the median duration of EAT

Reviewer comment 1.20
Discussion: -Last paragraph: I would clarify 90-day relapse rate. Also, the same wording is found in the abstract.

Author response 1.20
We agree with the reviewer that the word "rate" may be unnecessary and has consequently been removed from the paper.
The following has been changed in the manuscript: -Were stats not performed on Definitive Therapy Drug?

Author response 1.22
Thank you for this question Although highly relevant, analyses on definitive therapy were not performed as this study specifically addressed the effect of EAT and thus evaluation of definitive therapy on the clinical outcome of SAB is beyond the scope of the present paper.

Reviewer comment 1.23
Tables: -Notate PS matched in the title where applicable

Author response 1.23
We agree with the reviewer that the would be appropriate to include "propensity score-matched" in the title of relevant tables.
The following has been changed in the manuscript:

Reviewer #2
Summary: This is a thoughtful multicenter retrospective cohort study that seeks to address the timely issue of empiric antimicrobial therapy, particularly the initiation of a beta-lactam, while balancing risk of mortality from S aureus bacteremia.
The study is strengthened by its long study period and large cohort which increases the study's extrinsic validity. It is also enhanced by utilizing propensity matching to address confounding by indication, which strengthens the internal validity of the study. This allows readers to better understand how to contextualize the study's findings and apply them to their own practice.

Reviewer comment 2.1
To strength the paper, I would recommend commenting on the following: -The study's clarity could be enhanced with the addition of explanations or enhanced precision of language to certain terms such as "blood parameters" or the clinical or research relevance of identifying healthcare-associated SAB as a distinct entity.

Author response 2.1
Thank you for reviewing our manuscript and for the very useful comments.
Regarding precision of language, please see author response 2.7.
Regarding healthcare-associated SAB, please see author response 2.4.

Reviewer comment 2.2
-To further succinct and relevant communication of statistical information, consolidating tables such as 2 through five and reviewing how certain supplementary figures/tables or figures contribute to the results of interest. This would allow the addition of data that could not be shown to be presented and contribute further to the study's published findings.

Author response 2.2
Excellent suggestion. We agree that consolidating the five tables included in the manuscript could enhance the overview of study data. Tables 2 and 3 and tables 4 and 5, respectively, show different   data on the same cohorts. Therefore, tables 2

and 3 and tables 4 and 5 have been merged into an A
and B section.
The following has been changed in the manuscript:

Reviewer comment 2.3
Major essential revisions: Abstract and Importance -Would state at the start that the study assesses MSSA rather than MRSA to ensure readers are aware of the pathogen at hand; international readers in areas with a predominance of MRSA may suppose MRSA over MSSA at the start.

Author response 2.3
Thank you for this comment. Please see author response 1.1.

Reviewer comment 2.4
Methods -Please clarify in the definitions why it was important to define a health-care associated SAB in contrast to hospital and community onset as health-care associated SAB is not brought up later in the paper as an entity with notably differences in clinical outcomes.

Author response 2.4
Thank you for this comment. Healthcare-associated acquisition has been recognized as a separate acquisition group in prior studies on bacteremia and in particular SAB. (1,(12)(13)(14)(15)

Reviewer comment 2.5
-Please provide exclusion criteria in this section.

Author response 2.5
We agree with the reviewer that exclusion criteria should be stated clearly in the Method section.

Reviewer comment 2.6
-Would clarify whether "iv device infections" included both central line associated infections and peripheral access-associated, or only one of the two.

Author response 2.6
We agree with the reviewer that further clarification on the definition of iv device infections would be appropriate. For this study, iv device infections included both central and peripheral line- The following has been changed in the manuscript:

… 4) "iv device infection" (both central and peripheral)…
Reviewer comment 2.7 -Please clarify what is meant by "blood parameters" for the Pitt bacteremia score as there are temperature, blood pressure, mechanical ventilation, cardiac arrest, and mental status points but the terminology is not commonly used and could confuse some readers with its lack of specificity.

Author response 2.7
Thank you for this comment."Blood parameters" refers to blood test results, which were solely included in the SOFA score and not in the Pitt score. We agree with the reviewer that this could be specified in the manuscript.
The following has been changed in the manuscript: The clinical scores were based on vital signs and blood test results (only relevant for SOFA score) at MS-SAB onset, defined as the worst combined vital signs within 12 hours of blood culture testing and the worst blood test results within 24 hours of blood culture testing.

Reviewer comment 2.8
-Please clarify why two clinical scores were utilized and calculated.

Author response 2.8
We believe that the inclusion of two well-established clinical scores offers a comprehensive measure of the clinical severity of SAB. In a large study on community-onset bacteremia, the Pitt score has been shown to predict 28-day mortality. (16) The SOFA score is a widely-used tool to quantify the severity of sepsis.

Reviewer comment 2.9
-Please clarify why 3 days was chosen as the cutoff for duration of therapy.

Author response 2.9
Very relevant comment. The following has been changed in the manuscript: Cutoff for the duration of EAT was set to three days because results from both blood culture and in vitro susceptibility tests would usually be available at this point. Any continuation of EAT after two days was therefore considered as prolonged EAT.

Reviewer comment 2.10
Results: -Would recommend keeping description of inclusion and exclusion criteria to the methods section for paper organization.

Author response 2.10
Thank you for this comment. Description of inclusion and exclusion criteria has now been removed from the Results section.
The following has been changed in the manuscript:  Table 3).

Reviewer comment 2.15
-Line 129: Would consider providing an example of a diagnosis that falls into the "other" category.

Author response 2.15
Thank you for this comment. The group of "other" indications for EAT consisted of a wide variety of clinical manifestations such as meningitis, CNS/lung abscess or endocarditis.
The following has been changed in the manuscript: … and 7) "other" (e.g. meningitis).

Reviewer comment 2.16
-Line 146: Please define or provide an example of what is meant by a serious S. aureus infection

Author response 2.16
We agree with the reviewer that the term "serious" S. aureus infection may be confusing and has now been changed into "severe" S. aureus infection, which was defined by the presence of a secondary manifestation such as osteomyelitis, arthritis, endocarditis, pneumonia or meningitis.
The following has been changed in the manuscript:

MS-SAB relapse was defined as a new episode of MS-SAB or other severe S. aureus infection after completion of antimicrobial therapy and < 90 days after the initial MS-SAB episode. A severe S.
aureus infection was defined by the presence of a secondary manifestation (e.g. endocarditis).

Reviewer comment 2.17
-Line 168: Exactly how many cases or controls were matched up against more than one case or control? For readers who may be unfamiliar with propensity score matching, would consider explaining briefly why multiple matches might have been required.

Author response 2.17
Thank you for this comment. Below is a

Reviewer comment 2.18
Results: -Line 181-182: Consider providing a specific odds ratio to quantify how much more likely were the TZP monotherapy group to have a higher CCI. Would also be specific in saying CCI rather than comorbidity itself as the score is a cumulative measure.

Author response 2.18
Thank you for this comment. We used the Charlson comorbidity index score as a total measure of the burden of comorbidity of the study population. We agree with the reviewer that it would be more accurate to state that the TZP group had a higher CCI score compared to the other therapy groups. An odds ratio of this relation has been added to the paper in order to quantify the higher CCI for the TZP group.
The following has been changed in the manuscript:

Reviewer comment 2.19
-Line 183: Please consider providing a specific odds ratio to quantify how much more associated "skin, soft tissue or bone infection" was associated with cefuroxime alone.

Author response 2.19
Thank you for this relevant comment comment. We agree with the reviewer that a specific odds ratio to quantify the association between the indication "skin, soft tissue or bone infection" and cefuroxime compared to TZP is relevant.
The following has been changed in the manuscript: "Skin, soft tissue or bone infection" was more often associated with administration of cefuroxime